An 11‐Protein Plasma Proteomic Signature Associated With Incident Dementia Risk in the UK Biobank

AIM: To derive a compact plasma proteomic signature associated with incident dementia and evaluate the internal performance of the finalized score in UK Biobank. METHODS: In this prospective cohort study, we screened 2923 baseline Olink assays using Cox models adjusted for age, age squared, sex, and the first 10 genetic principal components. Proteins passing false-discovery-rate control underwent 2- and 5-year landmark analyses, correlation-based redundancy pruning, and repeated stability-based feature selection. The finalized score was evaluated in basic and extended clinical models, a chronological subgroup performance assessment, proportional-hazards testing, and landmark sensitivity analyses. RESULTS: Among 36 696 participants (mean age 56.84 years; 591 incident dementia events; median follow-up 15.73 years), the final 11-protein score was associated with incident dementia (hazard ratio per 1-SD increase, 2.645; 95% confidence interval, 2.459-2.845) and increased Harrell's C-index from 0.798 to 0.862. In the extended clinical cohort (23 179 participants; 441 events), C-index increased from 0.792 to 0.861. In the later chronological subset (6954 participants; 97 events), C-index increased from 0.801 to 0.869. Associations persisted in the 2- and 5-year landmark analyses, and no statistically significant score-specific violation of the proportional-hazards assumption was detected (p = 0.105). CONCLUSIONS: A broad plasma proteomic screen yielded a compact 11-protein signature that was strongly associated with incident dementia and showed consistent internal performance after the score had been finalized. Independent external validation is required before clinical use.